Drug Discov Ther. 2026;20(2):190-198. (DOI: 10.5582/ddt.2026.01000)
Effects of Janus kinase inhibition and interleukin 6 inhibition on serum cytokine/chemokine in idiopathic multicentric Castleman disease
Fukui S, Sumiyoshi R, Koga T, Hosogaya N, Narita S, Morimoto S, Kamisawa O, Kiya R, Katsube A, Yano S, Kawakami A
Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disease characterized by systemic inflammation. Although IL-6 receptor blockade with tocilizumab is an established treatment, Janus kinase (JAK) inhibition may offer broader immunomodulation by targeting multiple cytokine signaling pathways. This comparative longitudinal study evaluated 41 serum cytokines/chemokines in 10 patients with plasma-cell-type iMCD (five treated with filgotinib (JAK1 preferential inhibitor) for 52 weeks and five treated with tocilizumab for a median of 28 months) to compare the cytokine/chemokine suppression profiles between these two mechanistically distinct therapies. Patient values were normalized to those of healthy controls (n = 101) using Z-scores. At baseline, both groups exhibited marked elevations in cytokines, including IL-12p70, IL-22, IFN-γ, and IL-6. Both treatments resulted in significant changes in multiple cytokines, with 12 cytokines showing significant changes in each group. Between-group comparison revealed only three cytokines with differential responses: IL-6 (receptor blockade artifact), IL-15 (greater suppression with filgotinib), and PDGF-AA (greater suppression with tocilizumab). Overall, cytokine suppression was equivalent between the treatments (median ΔZ-score: −0.32 (filgotinib) vs. −0.27 (tocilizumab), p = 0.74). Principal component analysis demonstrated parallel treatment trajectories toward normalization. These exploratory findings from this small-sample study suggest that JAK inhibition and IL-6 receptor blockade may achieve comparable broad-spectrum cytokine/chemokine suppression in iMCD, despite the different mechanisms of action. However, the discordance between cytokine suppression and clinical improvement with filgotinib suggests that complete IL-6 pathway blockade remains critical for the clinical response in iMCD, highlighting the need to identify additional pathogenic drivers beyond the measured cytokine network.
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